PL81227B1 - Quinazoline derivatives [gb1349136a] - Google Patents

Abstract

1349136 Quinazoline derivatives SANDOZ Ltd 2 Dec 1970 [5 Dec 1969 26 Aug 1970] 57221/70 Heading C2C Novel compounds of Formulµ I and II (in which each of Y, Y 1 and Y 2 is C 1-3 alkoxy and either each of R and R 1 is H, C 1-4 alkyl or a radical selected from where R 2 is H, -(CH 2 ) m -CH 3 or n is 1 to 6, m is 0 to 4, y is 1 to 4 and z is 1 to 4, provided that (i) at least 1 and not more than 2 nitrate groups are present, (ii) one of R and R 1 is H or alkyl when the other is a radical defined under (b) above, (iii) in any radical defined under (b) above which may be present, one and only one substituent R 2 has a meaning other than H, (iv) n+m is not greater than 6, and (v) n+y is not greater than 7, or R and R 1 , together with the adjacent nitrogen atom, represent a radical of Formula III and R 3 and R 4 have the same meaning as R and R 1 , respectively, except that each -ONO 2 group in R and R 1 is replaced by a hydroxy group) are prepared (a) by reacting a compound of Formula IV (in which Q is Cl, Br or WZ, where W is O or S and Z is alkyl, phenyl or benzyl) with an amine of formula HNRR 1 or HNR 3 R 4 , or (b) for compounds I, by nitrating compounds II. 3 - Bis - (2 - hydroxyethyl)aminopropylamine dinitrate ester is prepared by nitration of the corresponding hydroxy compound. Pharmaceutical compositions having antianginal activity and/or hypotensive/anti-hypertensive activity, for oral or parenteral administration, comprise a compound I or II, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutical carrier or diluent. [GB1349136A]

Description

81227 MKP C07d 51/48 Int.Cl2. C07D 239/94 Process for the preparation of 4-Amino-6,7,8-tralkoxyquinazolines. The present invention relates to a process for the preparation of 4-amino-6,7,8-tri? AlJk'oxychiTi? Zolline of formula I, wherein Y, Yi Y2 may be the same or different and represent an alkoxy radical of 1-3 carbon atoms, R and Ri are hydrogen, an alkyl radical of 1-4 carbon atoms, or groups of formula 13, formula 14 or formula 15, where R2 represents a hydrogen atom or a radical -n (CH2) m-CH3 or a group -H (CH2) y ^ ONO2, n is from 1 to 6, especially 3 to 5, m is from 0 to 4, y is from 1 to 4, and az represents the number 1-4, whereby one or a maximum of two nitrate groups are present, one of R and R 1 is a hydrogen atom or an alkyl radical, while the other is a group of formula 14, with the optionally present group of formula 14, R2 has a different meaning than hydrogen, the sum of which does not exceed 6 and the sum of n and y is not more than 7, or where R and Ri together with the nitrogen atom form the group of formula 16, wherein z is as defined above. Zjeidn. Am. No. 3,440,498, 4-aminoalMloaimmoquinazolines are known which are used as active substances in the production of pharmaceutical preparations. The compounds mentioned therein, however, differ greatly (in terms of their structure as well as in terms of medical indications from the compounds according to the invention.) The method according to the invention consists in the fact that suitable nitrates are appropriate. 4Hamiino-6,7,8-tralkoxyquinazoline hydroxyl derivatives of formula 2, wherein Y, Yi and Y2 have the meaning given above, and R3 and R4 have the same meaning (meaning as R and Ri, however each -ON02 group is replaced by the group ( hydroxy or appropriately substituted at the 4, 6, 7, 18 position - tri-alkoxyquinazoline of formula 8, where Y, Yi and Y2 have the meaning given, and Q is chlorine, bromine or the group - WZ in which W is oxygen or sulfur and Z is an alkyl, phenyl or benzyl radical, and is reacted with the amines of formula IV, in which R and R 1 are as defined above. The first variant of the process is based on a known nitration. typical nitrating agents that it splits off as a nitronium ion, for example nitric acid in the presence of carboxylic acid anhydride, preferably with 3 to 8 carbon atoms, cupric nitrate in the presence of acetic acid and also nitric acid in the presence of sulfuric acid. Preferably nitric acid is used in the presence of acetic acid anhydride. The reactions are preferably carried out in an organic solvent, for example a lower carboxylic acid, in particular acetic acid, or possibly also in an excess of carboxylic acid anhydride when this is part of the nitrating agent. The reactions are carried out in 812273 81227 4 ten times --10 ° to + 50 ° C, especially at a temperature of + 5 ° to + 20 ° C. Any nitrating agent according to the first variant of the method can also be used with a nitrate mixture of a suitable metal, such as such as sodium, copper or, preferably, silver nitrate and phosphorothioic acid diester chloride of Formula 5, where W is as defined above and R 2 is an alkyl radical of 1-4 carbon atoms, preferably an ethyl radical, preferably at temperature 20-1000 ° C, with acetone or acetonitrile being used as the solvent. Although this method is not particularly advantageous, it can be advantageously applied in the simplest cases, for example when} TJpMhmz & ~ a & 0m of consent, and Ri has a different significance and the IrutSMcK in fciII4 [Dru | is preferably carried out at a temperature of -10 ° C to + 100 ° C, in particular 10-8 fine-grained and acidic solvents. The solvent used is aromatic solvents such as benzene, cyclic ethers such as dioxane or lower alamols such as isopropanol. the latter is particularly conducive. It is also possible, if appropriate, to use an excess of the compound of formula IV as solvent when it is liquid under the reaction conditions. The reactions are preferably carried out in the presence of an inert acid-binding agent, such as sodium carbonate. The compounds of formula I can be isolated and purified in an alternate manner. The hydroxyl derivatives of 4HaminO-6.7, S-trialkoxy used in the first variant of the process are possible. The ntazolines of formula II can be obtained by reacting an appropriately substituted 4-position 6,7,8-thiri-aflycoxyquinazoline of formula III with the amines of formula 6, in which R3 and R4 are as defined above. an inert organic solvent, for example as described in the second method. Optionally, it is also possible to use the compound of formula 6 in excess if it is a liquid under the reaction conditions. The reactions are preferably carried out at a temperature of 20 to 150 ° C, especially 50 to 100 ° C - and in the presence of an acid binding agent, for example sodium carbonate. Used as starting compounds in the second variant, as well as for the preparation of compounds of formula II The appropriately substituted 4-position of the 6,7v8ttroylinazolines of formula III can be obtained by the reaction of 6,7,8-tralkoxyquinazolm-4 (3H) -one of formula 7, wherein Y, Yi and Y2 have the meaning given above with a conventional chlorinating or brominating agent, such as phosphorus oxychloride, or phosphorus oxychloride, which gives 4-chloro or 4HbroinKH6,7y8-triacinazoline of formula IIIa, where Y, Yi and Y2 are obtained. have the meaning given above, and X 'represents a chlorine or bromine atom, or by reaction of 4, chloro, or 4, bromo-6.7, H, trialkolxyquinoline of formula 3a with a hydroxyl derivative of formula 8, in which Z is as defined above, ¬ jac gas substituted with oxygen at the 4-position e ^ e ^ tralkoxyine zoline of formula IIIb, wherein Y, Yi, Y2 and Z are as defined above, or a 6,7,8-tri-alkoxyquinazoline-4 (3H) -ition of formula 9, wherein Y, Yi and Y2 are as defined above meaning, it is reacted with halogen derivatives of formula 10, in which Z is as defined above, and X is chlorine, bromine or iodine to give the 4-substituted thi-substituted 6,7,8-alcohol xyquinazoline of formula IIIc, wherein Y, Yi, Y2 and Z are as defined above. The starting compounds of formula 7 can be obtained by condensation of compounds of formula 11, in which Y, Yi and Y2 are as defined above, with formamide. The reactions are carried out in a known manner, for example by heating the reaction mixture at Boiling under reflux. Compounds of formula 9 are known or can be prepared in a known manner, for example by reacting compounds of formula 7 with phosphorus pysulfur in an inert organic solvent. Compounds of formula 11 are known or can be obtained. receive them in a known way. They are obtained, for example, by the reduction of the compounds of formula (12) in which Y, Yi and Y2 have the meaning given above. The reactions are carried out in a known manner, for example by catalytic hydrogenation, for example in the presence of a palladium catalyst supported on carbon. Compounds of formula 12 are known or can be obtained in a known manner. The free bases of compounds of formula I can optionally be converted into The known method of acid addition salts and vice versa. The compounds of formula I are pharmacologically active and can therefore be used as medicaments. They have a particularly antihypertensive effect, so that they are recommended to be used as pressure-reducing agents. therefore they are used as a means of dilating the coronary vessels. The daily dose used is, for example, 6 - 500 mg, preferably in 1.5 - (2,150 mg (2 - 4 times a day or in retarded form) portions). The compounds of formula I can also be used as anti-angina and as suitable prophylactic measures, the daily dose used being, for example, 04-60 mg, which is given in 0.025-30 mg portions 2-4 times a day or in delayed-release form The compounds which are given below in Examples 50 i, Ha, Ilib, and XXI are also anti-arrhythmic and therefore can be used as anti-arrhythmic agents. The daily dose used here is 3-100 mg, preferably administered. It is fed in portions of 0.75-50 mg 2-4 times a day or in a delayed-release meal. The compounds listed may be screened as the free bases or in the form of their pharmaceutically acceptable acid addition salts. Acceptable acid addition salts. there are 60 for example fumarates, maleates, methosulfb - nanates, nitrates or sulphates. The compounds listed above can be administered orally or parenterally and can be processed with conventional adjuvants and additives to obtain the appropriate form of treatment. A suitable tablet consists of, for example, 4- (3-idlh- (i2-hydroxyethyl) amajnopropyl) amino diimaleate dinitrate 5.7 # -trimethoxyquinazolline, 10 mg tragacanth, 107.5 mg lactose, 25 mg starch maize, 10 mg of talc and 2 to 5 mg of magnesium stearate. Due to their particularly favorable action with phamiacology, the compounds of the formula I are particularly unfavorable for the compounds of example I, Ha, Ilb, lic and lim. -i (3-xyethyl / -iaminopropylbamano- ^, 7, 8Hl] trymethxklsychinazoline. a) 2-Haminb-3,4-pir6-methx) -xymeityl benzoate. Mixture of 30 g of 2-nitm-3,4,5H benzoate, three-methoxy of symethyl, 100 ml of acetic acid and 2.5 g of 5% palladium on carbon are shaken with water at 60 ° C for 25 hours at 3.5 kg / can. Then the thesis of ixxi vacuum is drained away. The resulting residue is distributed between the methylene chloride and the excess sodium carbonate solution. The methylene chloride solution is dried and evaporated in vacuo and distilled (105 ° C. 5 × 10-3 mm) to obtain 2-aminoOH 3,4-5-tert-methoxymethyl benzoate as an oil. b) 6,7,82 hive: methoxyquin-isollino-4j (3H) -one. A solution of 24.2 g of 2-Hammio-3,4-5th benzoate (toxymethyl in 80 ml of 99% Howeformamide) is heated under reflux for 1.25 hours. The reaction mixture cools. I treat it with 200 ml of ice water, the body is drained steadily, washed with water and dried, obtaining a B ^ ^ - ^ tri-methoxycinisilinio ^ SHJ-one with a melting point of 220-222 ° C. c) 4 ^ htaio-6 , 7-8-thiromethoxyahine-aline. A mixture of 11.6 g of 6,7,8-trimethyloxyquinazol-4 (3H) -one and 40 ml of phosphorus oxychloride is heated for 20 minutes under reflux. The reaction mixture is cooled and an excessively diluted ammonia solution is added at 0 °. The mixture obtained is shaken at 0 ° C. with 350 ml of chloroform, the organic phase is dried and filtered through silica gel. After removing the solvent, 4-chloro-6,7,8-tri: methoxyquinazoline with a melting point of 110 ° C is obtained. d) 4- (3-di-): 24 [mu] gDthVamino-6,7,8Htrimethoxychinispholine. A mixture of 6 g of 4-chloro 6, 7, 8-1N: co-1 x) and xBycnmaEl] iine, 4.2 g of 2-di- (2-hydroxyethyl) -aminopropylamine and 3.5 g of sodium carbonate is heated in 30 minutes under reflux in 30 ml of boiling isopropanol. The reaction mixture is filtered, the solvent is removed under vacuum and the crystalline residue is recrystallized from ethyl acetate, giving 4- (13-nopropyl) amino-6.7, 8-trimethoxyquinazoline, m.p. 142-1440 e) 4- (3-di- (12- (hydirokisy)) thyl (aminopropyl) amino-6,7,8-thymethoxyquinazoline dinitrate. A solution of 6.42 g of 4- (3- "di- (2-hydroxyethyl) anthiinopropyl) anniino-6.7.8H-trimethoxycinazoQine in 30 ml of glacial acetic acid is added dropwise over 6 minutes to the stirred and cooled mixture. to a temperature of 3-10 ° C. of a mixture of 14.2 ml of acetic acid anhydride and 4.73 ml of 90% nitric acid. After the addition is complete, stirring is continued for a further 5 minutes, and the resulting mixture is added to 300 ml of a buffer mixture consisting of acetic acid solution and sodium acetate solution mixed in a 1: 1 molar ratio. The mixture thus obtained is extracted 3 times with 200 ml of ethyl acetate, then the combined extracts are washed at 3 ° with an excess of sodium carbonate solution, dried and evaporated under a vacuum, and the resulting solid residue is treated with a solution of 3.08 g of maleic acid. in 25 ml of ethanol. After the mixture thus obtained is evaporated under vacuum, the salty residue is retained, filtered and washed with cold, 0 ° ethanol, dried and recrystallized from methanol to give 4- (3- "di-) 2-sodium dinitrate bisaleate. Hydroxy-ethyl / aminopropyl / ammo-6 ^ 7,8-tri-methyl1x) kBychinocolines having a melting point of 107 ° C (decomposition). Example II By analogy to example I (unless otherwise stated) and using the appropriate starting products in the following compounds are obtained in a suitable amount: starting from 4- (6-hydroxyhexyl) amino, 7.8-mp 143-144 ° C (crystallization from ethyl acetate), 4- (6-) hydroxyhexyl (amino, 7,8-tetra) maleate at a temperature of to (106-107 ° C (crystallization from a mixture of ethanol and ethyl ether), from 4- (3-hydroxypentyl) ianine-6.7 Trimethoxyquinazoline, m.p. 143-144 ° C (crystallization from ethyl acetate), 4- (3-hydroxypenty) nitrate Vitaminb-6 sols in the form of moleate, mp. 110 ° C., (with decomposition) (crystallization by the addition of diethyl ether to the oily product), from 4- (4-hydroxybutyl), mp 174 to <174 ° C. 5 ° C (crystallization from ethyl acetate) 4- (4-hydroxybutyanoin-tetraethoxyquinazoline nitrate in the form of maleate, mp 1114-115 ° C (crystallization from a mixture of methanol and ethyl ether) and recrystallization from ethanol), from 4- (4- (2-hydroxyethyl) -yl-piperazine) -6.7 ^^ tr; jetolxyquin-aeolines, m.p. 100-1G2OC 4- (4-) i2hydrocyetyio / HlHpiperazine / - 6,7,8 Triethoxyquinazoin in the form of the dihydrochloride with a melting point of 170 ° C from 4- (5-hydroxyphyl) amdno, 7% of zoline with a melting point of 109-ill0 5 ° C 4- (S-hydroxypentyl nitrate) (amino-phyl-yS-4-triethoxyquinazoline in the form of a nitric acid addition salt, m.p. 78-79 ° C, with 4- (3-di- / 2-hydriolxyiethio-am, e, 3, triethoxyquinazolines) mp 93 ° -04 ° C. 4- (3-di (2-hydroxyethyl) (aminophenyl) amino-6,7,8-trietholxquinazoline dihydrate in the form of a dihydrate, mp 130 ° C. decomposition), from 4- (3-oVu (3-nyd;] X) xyp (ixpya) -6,7,8-trimethoxychmazoin with a melting point of 117-118 ° C. hydroxypropyl / am & nopropyl / amiino - 6.7, (8 - trimethoxychi 10 15 20 25 30 35 40 45 50 55 607 81227 8 nazolines with a melting point of 120—121 ° C (decomposed), with 4- / 4- di- (2-hydroxyethyl) aminobut ^ ^ ^ 7.8 ^ tethoxyquinazoline with a melting point of 159 ^ 160 deg. C 4- (4-di- (2-hydroxyethyl) amimobuftyio) amino-6.7 dinitrate, 8Htrimethoxycshmazoline in the form of the dihydrochloride (hygroscopic, therefore no melting point was reached), with 4- (4-hydroxy-methyl-5- "hydroxy (npenityl) -amino-6.7,8H-trietho-Bychin) azoMn with a melting point of 155 - <160 ° C. 4- (4-hydroxy) xnienyl-5-hydroxy (pentyl) amino-6,7,8-methyl nitrate in the form of a nitric acid addition salt, mp 114.5-115 ° C, with 4. N-mimetics (1-N- (3-hydroxyethyl) amino-polypropyl-amijiol-C 5 -methmethoxy quinazole, mp 80-91 ° C. 4- [N-methyl nitrate --N- (3-'dWu- / 2-Nydiroxye: thyoyl / alinine] -6.7.8 ^ 1xHymethoixyquinone (ropes in the form of furnarane, melting point 79-81 ° C, with 4-di- (2-hydox) xyetio-aimino-, 7.8-ohinazoline with a melting point of 110-ill3 ° C di-nitrate 4-w- (2-hydirolxye (thyl) -aimino-6.7.8-trniel1x) lk5quinazoline in the form of addition salt with nitric acid, m.p. 121-127 ° C (with decomposition), from 4- (2,3-dihydroxypropyl) n-xquinazoline, mp 185-186 ° C, 4- (2-3-df-dihydroxypTopyl) dinitrate (amino-6,7,8-trimethoxychio) 2 Iolines in the form of maleate, m.p. 130-140 ° C, from 4- (2-di- (5- "hydroxy) xoxy) (aminoethyl) amino-6,7,8-triomethoxByohinaz olines, m.p. 153 ° -154 ° C, 4- (2-di- (2-hydroxyethylaminoethyl) ammino, 7.8-triethyl dihydrochloride, mp 136 ° C. (with decomposition) Example III 4- (3 ^) di- (2-hydroxyethyl) (animopyropyla) amino-yoyhmethoxyquinanoate dinitrate. 0.05 g of 4- (3-di- (2-hydroxy) thi (aminopropyl) amino-6.7.8-6'-metholxychmazoyilin are suspended in a solution of 2 to 82 g of diethylphosphoro rhodvutionate in 30 ml of dry acetone under nitrogen. The mixture thus obtained is then treated with vortexing, 2.55 g of silver nitrate, the temperature being 25-30 ° C. The reaction mixture is then left under capping for an hour at room temperature, then the gummy mass obtained is dissolved in methanol and the solution is filtered to remove the silver chloride. The filtrate is evaporated and the residue is dissolved in 75 ml of chloroform, this is washed with ice-cold dilute ammonium hydroxide solution. The organic phase is dried and evaporated to give the title compound which, as described in Example I is converted into a dimelate salt having a melting point of 109.5-110 ° C (with decomposition) (recrystallization from methanol). Example IV. 4- (3-di- (2-hydroxyethy) (arninopropyio) ammonium nitrate (a) 4-ibromo, 6.7.8 I, tri-methoxyquinazoline. 10.5 g of phosphorus oxybromide are added portionwise at 70 ° to 1 g of 6.7-triethoxyquinazoline-4 (3H) -one, and the mixture thus obtained is then heated at 90 ° C for half an hour, and then Pour into a flask containing 5 ice and 25 ml of ammonium hydroxide solution. The aqueous layer is extracted three times with methylene chloride and, after drying the organic extracts over magnesium sulphate, the solvent is evaporated and recrystallized from chloroform to give the compound stated in a title with a melting point of 107-108 ° C. b) 3'-di- (2-hydroxyethyl) aminopropylamine dinitrate. A solution of ILL, 3 g of 3-din (2-chydrooxyethyl) aminopropylamine in 8 ml of tetrahydrofuran is added over 15 minutes at 0-5 ° C to a mixture of 49 ml of acetic anhydride and 16.3 ml of 9 t ( [mu] l nitric acid The reaction mixture is then left for 45 minutes at -6 ° to -10 °, 500 ml of dry diethyl ether are added with stirring, the mixture is stirred for a further HO minutes, the ether layer is decanted and the remaining oil is treated with 500 ml * ice water. The solution obtained is neutralized with solid sodium carbonate, saturated with sodium chloride and extracted twice with ethyl acetate, 50 ml each. The extracts are dried over magnesium sulphate and, after evaporation of the solvent, the an oil from which the title compound is obtained as an oil by chromatographic purification with silica gel.c) 4- (3-di- (2-hydroxyethyl) -amino-propyl) amino, 7.8- dinitrate triethoxyquinazolines. 2.7 g of 3-di- (2-hydroxyethyl) amino propylamine dinitrate are dissolved in 5 ml of dioxane and 0.96 g of 4-bromo, 7.8- - • triethoxyquinazoline is added to the solution obtained. The reaction mixture is stirred overnight and then 100 ml of chloroform are added. The solid is filtered off and the residue is left with an oil which is redissolved in chloroform to remove residual dioxane and evaporated. The oil obtained is chromatographed on silica gel using a 90: 1 and 98: 2 mixture of chloroform and methanol as eluent. The resulting solution 45 is evaporated and the residue dissolved in 20 ml of methanol and this solution is treated with 0.385 g of maleic acid in 15 ml of methanol. The mixture is then filtered, the filtrate is evaporated, the residue is treated with 100 ml of diethyl ether at the temperature of an ice bath and the obtained crystalline material is filtered off and washed with a 1: 1 mixture of methanol and diethyl ether and dried at high temperature. vacuum. The bivalate of the title compound is obtained, which melts with decomposition at 107 ° C. Example 5 By analogy with example IV, the following compounds are obtained by using the appropriate starting products in the amounts used: 60 nitrate 4 (5-hydroxyhexyl) amino-6,7,8-trimethoxyquinazoyline in the form of maleate, m.p. 106-107 ° C (crystallization from a mixture of ethanol and ethyl ether), 4- (4- (2-hydroxyethyl) -l nitrate -ipiperazine / -6,7,8- 65 -triethoxy-quinisoline in the form of dihydrochloride-9 81227 10 with a melting point of 170 ° C (decomposed), 4- / 3-di- / 2-hyid nitrate, TitokByethyl / ajmdn <) pyropyIo (amino), 7.8% -tokisyquinazaline dihydrochloride, m.p. 130 ° C (decomposition), 4- (4H-hydroxyimethyl) 5-hydroxy (pentyl) amino-6.7.8% triimethoxBiquinazoline in the form of with a nitric acid addition hall, mp 114.5-115 ° C, 4- [NHmethyl-N- (3-di- (2-hydroxy) k6-ethyl) dinitrate / 10 am inopropylamino] -8,7, i8-tr6fmethokBych) inazoline in the form of fujmuirane, m.p. 79——e ° C, 4-di- (2-hydroxyethyl) aminOJ6,7,8-thooyhmethoxyquinazoyiline in the form of a nitric acid addition salt with a melting point of 121 ° -122 ° C (decomposition), 4- (5-hydroxybypentyl) amiino-6.7.8Htir6imethytofcsquinazoline azolane in the form of a maieate with a melting point of 110 ° C (decomposition), (crystallization in 20 by adding diethyl ether to the oily product), 4- (4-ihydroxyibutyl) aminoH6.7.8- tr6-thimethoxyquinazoline nitrate in the form of a thymethoxyquinazoline, m.p. 114-1-15 ° C (crystallization from a mixture of methanol and ethyl ether and recrystallization from ethanol), 4- (5-xychimazoline nitrate in the form of nitric acid addition salt, m.p. 78-79 ° C, 4- (3H-di- (3-hydro] XDl-xypropyl) aminopropyl) amino-6.7 dinitrate , 8- (tri-methyl) melting point 120 ° -121 ° C, 4- (4-di (2-hydroxyethyl) dinitrate, non-bultil (amino-e, 5) - tetra-methoxychmazolki in the form of dihydrochloride (hygroscopic, therefore no melting point is possible), 4- (i2,3-dihydroxy) dinitrate) xypanopyla (mino-6.7, 8-thymethoxy methoxide, melting point, melting point 139) 140 ° C, * 4- (2-dihydro (2-hydroxy-methyl) aminoethyl) -amino-6,7,8-ttrimetho dinitrate (xiquinazoline in the form of dihydrochloride with a melting point of 136 ° C (decomposition). PL PL

Claims (29)

1. Claims 1. A method for the preparation of 4-amino, 7,8HteójaikokBy-cMnazolines of formula I, in which Y, Yi and Y2 may be the same or different and represent an alkoxyl radical with 1 to 3 carbon atoms, R and R 1 represent a hydrogen atom, an alkyl group of 1-4 carbon atoms or a group of the formula 13, formula 14, or the formula 15, where R2 is a hydrogen atom or a radical - (CH2) m -CH3 or -ICHrphs -ONO2, n represents the number 1-6, especially 3-5, m represents the number 0-4, y represents the number 1-4, and az represents the number 1-4, where, however, one or more than two groups are present nitrate, one of R and Ri represents a hydrogen atom or an alkyl radical, when the other is a group of formula 14, in the case of an optionally present group of formula 14, R2 has a different meaning than hydrogen, the sum of which does not exceed 6 and the sum is not is greater than 7, or in which R and Ri together with the nitrogen atom form a group of formula 16, in which z has the meaning given above, characterized in that it nitrates the corresponding derivative e hydroxyl 4-amino-6,7,6-triacinazolines of formula II, wherein Y, Yi and Y2 are as defined above, and R3 and R4 have the same meaning as R and Rx , however, each -ONO2 group is replaced by a hydroxyl group, or appropriately substituted at the 4-position of a 6,7,8-trialkoxyquinazoline of Formula III, where Y, Yi and Y2 are as defined above and Q is chlorine, bromine or -WZ group, where W is oxygen or sulfur and Z is an alkyl, ethylene or benzyl radical, is reacted with amines of formula IV, where R and R 1 are as defined above . 2. Method according to alternatives. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- {3-bis- ((2 -hydroixyethyl) -amino) ditrate, 4- [3-bis- (2-hydroxyethyl) Hammopropydo] -amino- is nitrated 6.7-8-ttrimetholxyquinazoline. 3. Way according to satr. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- (6-hydroxyhexylZ-ammo-CJ, -trimethoxycinazoline) nitrate, 4- (6-hydroxyhexyl) -amino-6,7,8-rthyrio xycninase. 4. Way according to satrz. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- (5-hydroxy-pentyl) -amino-6,7,8-phthenicelK) xychmazoline nitrate, 4- (6-hydro-pentyl) amine is not poisoned: 6,7y84! Rójme1x) - ksychinazoline. Process according to claim 1, characterized in that in the preparation of 4- (4-hydroxybUityl) -aminOH 6,7,8-! Trimethylxychmazole nitrate, 4- (4-hydroxybutyl) -amino, 7.8H, is filtered. , methoxyquinazoline. 6. Method according to replace. 4. A process according to claim 1, characterized in that 4- [4- (2-hydroxyeltyl) -1-pyepeezyrao], 7.8 is nitrate in the preparation of 4- [4- (2-hydroxyethyl] -) 1-piperazine [Beta] -6.7,8-triethoxyquinazoimne. 7. The method according to p. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- (5-hydroxy-pentyyl) -amino-6,7,8-trie-1x) xiquinazoline nitrate, 4- (5-hydroxypentyl) nitrate is nitrate. 8. The way according to zapitrz. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- [3-bis- (2-hydrocByethyl) -aminopyropy] -am methoxyquinazoline dinitrate, 4- [3-fois- (12-hydroxyethyl) -aminopropyl] - is nitrated amino, 7,8-tri, 1 x xychinazoline. 9. The method according to claim 4. A process according to claim 1, characterized in that in the preparation of 4- [3-tois- (3-hydroxypropyl) -ammo-propyl] -amino-, 1,2,7,8-tr6'-methoxyquinazoline dinitrate, 4n. propyl). 10. Method according to the provisions. 4. A process according to claim 1, characterized in that in the preparation of 4- [4-bis- (i2-hydroxyethyl) -aminobutyio] -ammo-6.7-8- yymethoxyquinazoline dinitrate, 4- [4Hbis- (2-hydroxyethyl) / Haminobutyyl] -ammo-6,7,8- (tri (mertx) lxyc; h! Mazol! I -ne. 11. The way according to zapitrz. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- [4-hydroxymethylbeta] -hydiitolxy / pentytoxy-quinazoline in the preparation of 4- [(4-hydroxyimethyl-) -hydrokEy / -perotyilo] -, »maino-6 ^ nazoline. 12. The method according to p. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- {N-methyl-N- [3-ibis- (2-hydro!] Lcbyethyl) -alpha., 7.8-trimethoxyquinazolines, 4- {N-methyl-N-mononitrate is - tylo-N- [3HbQB- / 2-hyo-olkByietyl / -amino-opylio] -amino} - < 6.7fi-trimethoxyquinaodine. 13. Way according to fall. 4. A process as claimed in claim 1, characterized in that in the preparation of 4-di (2-hydroxyeltyl) -amino-6.7,18-phthyl diisotate, 4-di- (2-hyo-oilffiyeityl) is nitrated; , 8-thymetholffiychinazoline. 14. Way according to zapltrz. 4. A process according to claim 1, characterized in that 4- (2,3-dihydTOxypropyl) -amino-6,7,8-trimine dinitrate is nitrated with 4- (2,3-dihydroxypropyl) -amino-6, 7,8-trimethoxyquinazoline. 15. The method according to p. 4. A process according to claim 1, characterized in that in the case of the preparation of diazolthane of N - [2-lphis-2'-hydroxyethyl / naminoe-xychmazoline, 4 - [! 2-fois- (2-hydroxyethyl) -aminoethyl] -amimo-6 is nitrated, 7.8-t 16. Way according to zapltrz. 4. A process as claimed in claim 1, characterized in that, in the preparation of 4- [34is- (2-hydroxyethyl) amphipropropyltoxyquinazoline, 4-bromo-6,7,8Htaroyhmethoxbyinazoline dinitrate, it is reacted with 3-bis- (2- - - hyooksye 17. The method according to p. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- (6-hydroxy-hexyl) -anomo-6,7,8-itogmetho-4-pho-mo- €, 7,8- (trinethoxy-quinazoline is reacted with (6-hydroxyhexyl) amine nitrate. 18. The method according to zastiriz. 4. A process as claimed in claim 1, characterized in that in the preparation of 4- [4- (2-hydroxyethyl) -1-piperazine] -6.7.8, orthyethoxyquinazoline, 4-phoromo-6.718-tri-methyl nitrate, reacted with 4- (2-hydroxyethyl) -lipiperazine nitrate. 19. The method according to claim 4. A process as claimed in claim 1, characterized in that in the case of the production of 4- [3-bis- (2-hydroxyethyl) -aminopropyl] -amino-6,7,8-triethoxyquinazoline, 4-phonomo-6,7,8, triethoxyquinazoylene react with [3-bis- (2-hydroxyethyl) narninopropyl] amine dinitrate. 20. The method according to claim 4. A process as claimed in claim 1, characterized in that in the case of the preparation of 4 - [(4-hydroxymethy-4-hydroxy-pentyl] -am ^ toOcsycndnazoline, 4-ibromo-6,7,8 -trimethoxyquinazoline dinisotate, it is reacted with dinisdane [/ 4 -hydroxymethyl-5-hydroxy-pentyl] -amine. 21. Self according to claim 4. A process as claimed in claim 1, characterized in that in the preparation of 4- {N-methyl-1o-N- [3-bis- (2-hydroxyethyl) -aiminopropyl] -aimino} -6,7,8-trimethoxyquinazoMny nitrate, 4 Trimethoxy-quinazoline is reacted with NH-methyl-o-N- [3-bis- (2-hydroxyethyl) amino-propyl] amine dithrate. 10 22. The method according to claim A process as claimed in claim 1, characterized in that in the case of the preparation of 4-di- (2-hydro) xythio) -ammo-6,7,8-tri-methyl1xDkBychiinazoyiline, 4-di- (2 -hydro) -ammo-6,7,8-triline dinitrate with di- (2-hydroxyethyl) amine dinitrate. 23. The method according to claim A process as claimed in claim 1, characterized in that in the preparation of 4- (5-hydroxy-penityl) -amine, o-6,7,8-ttrium, methoxyohydnazoline, 4-armimio-e ^^ - tThymethoxyquinolithine nitrate is reacted with nitrate (5-hyd [oxypentyl] amine. 24. The method according to claim 4. A process according to claim 1, characterized in that in the preparation of 4- (4-hydirocBy-butyl-Z-ammo-G4 -S-1, -thimethoxyquinazoline, 4H-bromo-6,7,8-trimethoxyquinazoline) nitrate, it is reacted with nitrate / 4-hydroxybuty. ) o / -amiiny. 25. The method according to claim 3. A process as claimed in claim 1, characterized in that in the preparation of 4- (5-hydroxy-penityl) -amino-6,7,8-triethoxyquinazoine, 4-bi-mo-6,7,8-trimethoxyhinaiiline nitrate is reacted with (5-hydroxypenityl) -aimine nitrate. 26. The method according to claim 4. A process as claimed in claim 1, characterized in that, in the preparation of 4- [3'bds- (3-hydroxypropyl) -amin'opropyl) O] -amino-6,7,8H-trimethoxyquinazold, 4-bromo-6,7,8 The -Jtro} methoxychftazoline is reacted with [3-ibis- (S-hyidroxypropopyyl)] aminopropyl amine dinitrate. 27. The method according to claim 4. A process as claimed in claim 1, characterized in that in the preparation of 4- [4-tods (2-hydroxyethyl) ammobutyl] amdno-6.7-8Htrimethoxyquinazolates, 4-ibromo-6.7,8Htrimobutylinazolane, the reaction is with [4-bis- (2-hydroxyethyl) -aminobutyiLo] amine dinitrate. 28. The method according to claim 4. A process as claimed in claim 1, characterized in that in the preparation of dinitrate 4- (2,3-dihydroxypropyl) α-mmo-6,7,8-trimethoxy quinazoyiline, 4-bromo-6y7,8itriii-methoxyquinazoline is reacted with dinitrate ( 2,3-dihydroxypropyyl) -aimine. 29. The method according to claim 4. A process as claimed in claim 1, characterized in that in the preparation of 4- [2-bis- (: 2-hydroxyethyl) -aminoethyl] -amino-6,7,8-triethoxyquinoline, 4-bromo-6.7 , 8-trimethoxyquinazoline is reacted with [2-bis- (2-hydroxyethyl) -aminoethyl] -amine dinitrate. 81227 FORMULA 1 FORMULA 2 oz FORMULA 3b s — with FORMULA 3c HN — RI FORMULA 4 CL — P, / ° R5 U ^ OR W s PATTERN 5 HN-R3 PATTERN 6 ZOH PATTERN 8 PATTERN 981227 zx PATTERN 10 _CH2 (-CH2) n-ON02 PATTERN 13? • _CH2 (-CH) n-ON02 PATTERN 14 -CH2 (-CH2 ) zN = [- CH2 (-CH2) z-ONQ2] 2 FORMULA 15 -N N-CH2 (-CH2) z-ONO? MODEL 16 National Printing House, Plant No. 6, residing in 2887/75 Price PLN 10 PL PL